Device and Method for the Ablation of Fibrin Sheath Formation on a Venous Catheter

ABSTRACT

An indwelling venous catheter and method capable of destroying undesirable cellular growth is provided. The catheter includes a shaft having at least one lumen and adapted to be placed inside a vein for long term use. A plurality of electrodes are positioned near a distal section of the shaft and are adapted to receive from a voltage generator a plurality of electrical pulses in an amount sufficient to cause destruction of cells in the undesirable cellular growth that have grown around the shaft. In one aspect of the invention, a probe is configured to be removably insertable into the at least one lumen and the electrodes are positioned near the distal section of the probe.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. Section119(e) to U.S. Provisional Application Ser. No. 61/074,504, filed Jun.20, 2008, entitled “Device And Method For The Ablation Of Fibrin SheathFormation On A Venous Catheter Using Electroporation”, which is fullyincorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a medical device and method for thedestruction of undesirable cellular growth on a venous catheter, such asfibrin sheath formation and/or infectious cells, by delivering aplurality of electrical pulses.

BACKGROUND OF THE INVENTION

Catheters, and more particularly, venous access catheters have many veryimportant medical applications. For example, if a patient requireslong-term dialysis therapy, a venous access catheter, such as a chronicdialysis catheter, will be implanted in a patient's body. Chronicdialysis catheters typically contain a polyester cuff that is tunneledbeneath the skin approximately 3-8 cm and helps to anchor the dialysiscatheter to the body. The chronic dialysis catheter is connected to adialysis machine when the patient is treated. Hemodialysis is a methodfor removing waste products such as potassium and urea from the blood,such as in the case of renal failure. During hemodialysis, wasteproducts that have accumulated in the blood because of kidney failureare transferred via mass transfer from the blood across a semi permeabledialysis membrane to a balanced salt solution.

In another example, a venous catheter can be used in combination with animplanted port. A port can be implanted in patients that requirefrequent access to the venous blood, such as chemotherapy patients. Animplanted port includes attachment means for fluidly connecting acatheter. The port is implanted in a surgically created pocket withinthe patient's body and has a reservoir for delivering fluids through thecatheter. One end of the catheter is connected to the port, and theother end terminates in a vein near the patient's heart.

Another example of a long-term venous access catheter is a peripherallyinserted central catheter, also known as a PICC line. PICC lines areplaced in patients requiring long-term access for the purpose of bloodsampling and infusion of therapeutic agents including chemotherapeuticdrugs.

Notwithstanding the importance of venous catheters, one problem that isassociated with their use is the undesired formation of fibrin sheathsalong the catheter wall. See, for example, Savader, et al., Treatment ofHemodialysis Catheter-associated Fibrin Sheaths by rt-PA Infusion:Critical Analysis of 124 Procedures, J. Vasc. Interv. Radiol. 2001;12:711-715. Fibrin sheath formation is an insidious problem that canplague essentially all central venous catheters. It has been reportedthat fibrin sheath formation occurred as early as 24 hours aftercatheter placement and that this phenomenon was seen on 100% of centralvenous catheters in 55 patients at the time of autopsy.

The growth of a fibrin sheath along a catheter shaft can prevent highflow rates, adversely affect blood sampling and infusion ofchemotherapeutic drugs, and provide an environment in which bacteria cangrow, which may result in infections. Despite fibrin sheath build up,infused fluids may still enter the blood circulation, but when negativepressure is applied, the fibrin sheath can be drawn into the catheter,occluding its tip, thereby preventing aspiration. Complete encasement ofthe catheter tip in a fibrin sheath may cause persistent withdrawalocclusion. This can lead to extravasation of fluid where fluid entersthe catheter to flow into the fibrin sheath, backtracks along theoutside of the catheter, and exits out of the venous entry point andinto the tissue. The presence of a fibrin sheath on the catheter shaftmay also result in difficulty removing the venous catheter, particularlyPICC lines, from the patient.

Often patients who need prolonged intravenous regimens have compromisedperipheral venous access and thus venous catheters are often the onlymeans available for the delivery of necessary treatment. Therefore, suchvenous catheters should be configured to remain in a patient so thatdrugs and other fluids can be effectively delivered to the patient'svasculature and to break up any fibrin sheath growth.

There are a number of different techniques that have been developed toaddress the fibrin sheath-impaired venous access catheter. Thesetechniques include new catheter placement, catheter exchange over aguide wire, percutaneous fibrin sheath stripping, and thrombolytictherapy. For example, fibrin sheaths may be removed by mechanicaldisruption or stripping with a guidewire or loop snare, or by replacingthe catheter. Mechanical disruption can help prevent the need to replacethe catheter, and thereby eliminate disruption to the patient. However,mechanical disruption may not be effective because the fibrin sheath maynot be completely removed and often causes damage to the catheter shaftand vessel wall. Mechanical removal of fibrin build-up may also increasethe risk of embolism due to free floating debris within the vessel.

Replacing the catheter is also an option, but this can cause increasedtrauma to the patient, increased procedure time and costs, increasedrisks of pulmonary emboli, and may require numerous attempts beforeremoval is successful. Thus, both mechanical disruption and catheterreplacement may adversely affect a patient's dialysis schedule, causepatient discomfort, and loss of the original access site. Drug therapiesthat address the fibrin sheaths can also result in complications and areunreliable.

Therefore, it is desirable to provide a device and method for thedestruction of undesirable cellular growth on a venous catheter in asafe, easy, and reliable manner without having to remove the catheterfrom the patient and without damaging the vein or catheter itself.

SUMMARY OF THE DISCLOSURE

Throughout the present teachings, any and all of the one, two, or morefeatures and/or components disclosed or suggested herein, explicitly orimplicitly, may be practiced and/or implemented in any combinations oftwo, three, or more thereof, whenever and wherever appropriate asunderstood by one of ordinary skill in the art. The various featuresand/or components disclosed herein are all illustrative for theunderlying concepts, and thus are non-limiting to their actualdescriptions. Any means for achieving substantially the same functionsare considered as foreseeable alternatives and equivalents, and are thusfully described in writing and fully enabled. The various examples,illustrations, and embodiments described herein are by no means, in anydegree or extent, limiting the broadest scopes of the claimed inventionspresented herein or in any future applications claiming priority to theinstant application.

Disclosed herein are devices for delivering electrical pulses fordestruction and/or removal of undesirable cellular growth formations ona venous catheter and methods of using such. In particular, according tothe principles of the present invention, an indwelling venous cathetercapable of destroying undesirable cellular growth is provided. Thecatheter includes a shaft having at least one lumen and adapted to beplaced inside a vein for long term use. A plurality of electrodes arepositioned near the shaft and are adapted to receive from a voltagegenerator a plurality of electrical pulses in an amount sufficient tocause destruction of cells in the undesirable cellular growth that havegrown around the shaft. In one aspect of the invention, a probe isconfigured to be removably insertable into the at least one lumen andthe electrodes are positioned near the distal section of the probe.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of an electroporation venous catheter ofthe current invention with a plurality of electrodes at the distalsegment of the catheter.

FIG. 1B is an enlarged cross-sectional view of an electroporation venouscatheter taken along line A-A of FIG. 1A showing the arrangement of theelectrically conducting elements within the catheter shaft wall.

FIG. 2A is a perspective view showing an electroporation venous catheterof the current invention with electroporation electrodes implanted inthe body of a patient.

FIG. 2B is an enlarged view of the distal portion of the catheter ofFIG. 1A exhibiting fibrin sheath formation.

FIG. 3A is a partial longitudinal plan view of the distal segment of theelectroporation venous catheter showing the arrangement of electrodesand electrically conducting elements.

FIG. 3B is an enlarged cross-sectional view of the electroporationvenous catheter taken along line B-B of FIG. 3A showing the attachmentbetween an electrode and an electrically conducting element.

FIG. 4 is a partial plan view of the distal segment of theelectroporation venous catheter of FIG. 1A showing the electrical fieldpattern created when all electrodes are simultaneously energized.

FIG. 5 is a partial longitudinal view of the distal segment of theelectroporation venous catheter showing the electrical field patterncreated when only two electrodes are energized.

FIG. 6A is a plan view of an electroporation electrode proberepresenting another embodiment of the current invention.

FIG. 6B is a partial longitudinal cross-sectional view of the distalsegment of a venous catheter with the electroporation electrode probe ofFIG. 6A inserted through the catheter lumen and positioned within afibrin sheath formation.

FIG. 7A is an enlarged longitudinal cross-sectional view of anelectroporation electrode probe representing yet another embodiment ofthe current invention.

FIG. 7B is an enlarged longitudinal cross-sectional view of theelectroporation electrode probe of FIG. 7A illustrated electrodes in adeployed position.

FIG. 7C is a partial longitudinal cross-sectional view of the distalsegment of a venous catheter with the electroporation electrode probe ofFIG. 7A inserted through the catheter lumen with deployed electrodespositioned around the distal segment of the catheter.

FIG. 8 is a distal end view of the venous catheter shown in FIG. 7Cillustrating the electrical field pattern created when the deployedelectrodes are energized.

FIG. 9 is a flowchart depicting the method steps for fibrin sheathdestruction using the electroporation catheter of FIG. 1A.

FIG. 10 is a flowchart depicting the method steps for fibrin sheathremoval using the electroporation electrode probe of FIG. 6A or 7A.

FIG. 11 is a treatment setup for a patient for synchronization of thedelivery of electroporation pulses with a specific portion of thecardiac rhythm.

DETAILED DESCRIPTION OF THE INVENTION

Electroporation is defined as a phenomenon that makes cell membranespermeable by exposing them to certain electric pulses. As a function ofthe electrical parameters, electroporation pulses can have two differenteffects on the permeability of the cell membrane. The permeabilizationof the cell membrane can be reversible or irreversible as a function ofthe electrical parameters used. Reversible electroporation is theprocess by which the cellular membranes are made temporarily permeable.The cell membrane will reseal a certain time after the pulses cease, andthe cell will survive. Reversible electroporation is most commonly usedfor the introduction of therapeutic or genetic material into the cell.Irreversible electroporation, also creates pores in the cell membranebut these pores do not reseal, resulting in cell death.

Irreversible electroporation has recently been discovered as a viablealternative for the ablation of undesired tissue. See, in particular,PCT Application No. PCT/US04/43477, filed Dec. 21, 2004. An importantadvantage of irreversible electroporation, as described in the abovereference application, is that the undesired tissue is destroyed withoutcreating a thermal effect. When tissue is ablated with thermal effects,not only are the cells destroyed, but the connective structure (tissuescaffold) and the structure of blood vessels are also destroyed, and theproteins are denatured. This thermal mode of damage detrimentallyaffects the tissue, that is, it destroys the vasculature structure andbile ducts, and produces collateral damage.

Irreversible and reversible electroporation without thermal effect toablate tissue offers many advantages. One advantage is that it does notresult in thermal damage to target tissue or other tissue surroundingthe target tissue. Another advantage is that it only ablates cells anddoes not damage blood vessels or other non-cellular or non-livingmaterials such implanted medical devices (venous catheters for example).

Fibrin sheaths that form on venous catheters are primarily made up ofsmooth muscle cells with membranes. Therefore, destruction of the fibrinsheath by irreversible electroporation without causing any thermaleffects is a viable method of treating fibrin growth. It is alsopossible to destroy the cellular structure of fibrin sheath formationsusing reversible electroporation combined with a drug. This process isknown as electroporation-mediated chemotherapy and has been used tointroduce chemotherapy drugs into a tumor at an intracellular level.What has not been previously described is the use ofelectroporation-mediated chemotherapy for the introduction oftherapeutic agents, such as cytotoxic agents, into healthy butundesirable tissue such as the smooth muscle cells of a fibrin sheathformation. Cytotoxic agents are transported into the interior of thecell through the transient pore formations, ultimately causing celldeath. In this manner, the underlying cellular structure of a fibrinsheath formation can be destroyed by the introduction of cytotoxicagents into the smooth muscles cells comprising the sheath.

Although the following example discusses using the present invention andmethod to destroy fibrin sheath growth, persons of ordinary skill in theart will appreciate that the present device and method can treat anyundesirable cellular growth, including infectious cells.

FIG. 1A illustrates an indwelling electroporation venous catheter 10with fibrin sheath destruction capabilities. The catheter 10 iscomprised of a catheter shaft 25 that extends from a distal end opening28 to a bifurcate hub 49 and two extension tubes 30, 32. The extensiontubes 30, 32 terminate at hub connectors 34, 35 for connection to adialysis machine. Clamps 41, 42 serve to close off the extension tubes30, 32 between dialysis sessions. The catheter shaft 25 has at least afirst withdrawal lumen 16 and a second supply lumen 18, which share acommon internal septum 24, as illustrated in FIG. 1B. First lumen 16 andsecond lumen 18 extend longitudinally through substantially the entirelength of the catheter shaft 25, terminating at distal openings 26 and28, respectively. Side holes 31 and 33 provide supplemental access tolumens 16 and 18, respectively. FIG. 1B depicts a cross-sectional viewof the catheter taken along lines A-A of FIG. 1A illustrating theDouble-D lumen shape. Although the cross-sectional lumen configurationshown is a Double-D shape, it is contemplated that lumens 16 and 18 ofcatheter 10 may have any suitable cross-section lumen shape as requiredfor the particular use of catheter 10.

Catheter 10 includes an electrical connector 500 extending proximallyfrom hub 49 and in the illustrated embodiment positioned between theextension tubes 30 and 32. Catheter 10 also includes a plurality ofelectrodes 150 attached to the outer surface of the catheter shaft 25.The location of the electrodes on the catheter may be anywhere along theshaft, but the electrodes may generally be located near the distalsection of the shaft where the fibrin sheath formation most severelycompromises the fluid flow of the device. Furthermore, the size andshape of the electrodes can vary. For example, the electrodes can bering-shaped, spiral-shaped, or can exist as segmented portions. Theelectrodes may also be a series of strips placed longitudinally alongthe catheter shaft surface. The electrodes may be comprised of anysuitable electrically conductive material including but not limited tostainless steel, gold, silver and other metals.

A plurality of electrically conducting elements (e.g., electrical wires)160, shown in FIG. 1B, extend longitudinally within the wall of thecatheter shaft and function to connect each electrode 150 to a source ofelectrical energy in the form of a generator (not shown) by connectionthrough the electrical connector 500. Each electrically conductingelement 160 extends from an electrode 150 to which it is connected toterminate in electrical connector 500. An extension cable (not shown) isattached to electrical connector 500 to complete an electrical circuitbetween the electrodes 150 and the electrical generator through theelectrically conducting elements 160. The electrically conductingelements 160 may be comprised of any suitable electrically conductivematerial including but not limited stainless steel, copper, gold, silverand other metals. The catheter shaft is comprised of a non-conductivematerial such as urethane, and functions as an electrical insulatorinsulting each electrically conducting element 160 from the otherelements 160 and ensuring that the energy is directed to the exposedelectrodes.

FIGS. 2A and 2B illustrate an indwelling electroporation venous catheter10 of FIG. 1A implanted in the body of a patient 400. Catheter 10 isinserted into vein 404 of a patient 400 with the distal portion of thecatheter 10 located at the junction of the superior vena cava 408 andthe right atrium of the heart 412, where blood volume and flow rates aremaximized. FIG. 2B illustrates fibrin sheath formation 200 attached tothe outer wall 25 of the distal segment of catheter 10. As illustrated,the fibrous material occludes the distal end holes 26 and 28 and sideholes 31 and 33, thus impairing the functionality of the catheter.Fibrin sheath formation 200 may originate anywhere along the cathetershaft 25 where platelet aggregation begins. For example, fibrin sheathgrowth 200 may originate at the distal end of the catheter and thendevelop into a matrix of smooth muscle cells which can block the distalopenings 26, 28 and side holes 31 and 33 of the catheter 10.

The electrodes 150 are adapted to administer electrical pulses asnecessary in order to reversibly or irreversibly electroporate the cellmembranes of the smooth muscle cells comprising the fibrin sheath 200located along the outer surface of catheter shaft 25 or inside of thecatheter shaft 25 within a treatment zone. By varying parameters ofvoltage, number of electrical pulse and pulse duration, the electricalfield will either produce irreversible or reversible electroporation ofthe cells within the fibrin sheath 200. The pulse generator of thepresent invention can be designed to deliver a range of differentvoltages, currents and duration of pulses as well as number of pulses.Typical ranges include but are not limited to a voltage level of between100-3000 volts, a pulse duration of between 20-200 microseconds (morepreferably 50-100 microseconds), and multiple sets of pulses (e.g. 2-5sets) of about 2-25 pulses per set and between 10 and-500 total pulses.The pulse generator can administer a current in a range of from about2,000 V/cm to about 6,000 V/cm. The pulse generator can provide pulseswhich are at a specific known duration and with a specific amount ofcurrent. For example, the pulse generator can be designed uponactivation to provide 10 pulses for 100 microseconds each providing acurrent of 3,800 V/cm +/−50% +/−25%, +/−10%, +/−5%. The electroporationtreatment zone is defined by mapping the electrical field that iscreated by the electrical pulses between two electrodes.

When electrical pulses are administered within the irreversibleparameter ranges, permanent pore formation occurs in the cellularmembrane, resulting in cell death of the smooth muscle cells of thefibrin sheath. In another aspect, by proactively administering theelectrical pulses according to a predetermined schedule, fibrin sheathgrowth 200 on the catheter can be prevented altogether. Alternatively,electrical pulses may be administered within a reversibleelectroporation range. Cytotoxic drugs, such as a chemotherapy agent,may be administered through either catheter lumen into the volume offibrin sheath during the electroporation treatment. Temporary pores willform in the cellular membranes of the smooth muscle cells comprising thefibrin sheath, allowing the transport of the drug into the intracellularstructure, resulting in cell death.

FIG. 3A illustrates an enlarged partial plan view of the distal segmentof the electroporation venous catheter 10 with fibrin sheath removalcapabilities. A plurality of electrodes 150 are disposed on the outersurface of the distal portion of the catheter shaft 25. The electrodes150 are shaped as rings coaxially surrounding the catheter shaft. Inthis embodiment, each electrode 150 is individually electrically coupledto an electrically conducting element 160. As an example, the distalmost electrode 150A is connected to electrically conducting element160A, which extends within the side wall of the catheter shaft 25 fromelectrical connector 500 (FIG. 1A) to electrode 150A. Electricallyconducting element 160B extends from connector 500 and terminates atelectrode 150B. Electrode 150C, as shown, circumferentially surroundsthe outer walls of both lumens 16 and 18 and is electrically coupled toelectrically conducting element 160C which terminates in the catheterside wall at the location of electrode 150C. Similarly, electrode 1500,150E and 150F are electrically coupled to conducting elements 160D, 160Eand 160F respectively.

FIG. 3B depicts an enlarged cross-sectional view of catheter 10 takenalong lines B-B of FIG. 3A at the location of electrode 150D. Cathetershaft 25 is comprised of lumens 16 and 18 separated by a septum 24.Coaxially surrounding shaft 25 is ring electrode 150D. Electricallyconducting elements 160A, 160B, 160C and 160D are also illustratedembedded within the catheter shaft 25 wall. The catheter shaft 25 iscomprised of a non-conductive urethane material and functions as anelectrical insulator insulting each electrically conducting element fromthe other elements and from those electrodes 150 not physically coupledto the conducting element. Electrically conducting element 160D is shownin FIG. 3B as being electrically coupled to electrode 150D by anelectrically conductive material 320. To create the coupling, thecatheter shaft 25 surface may be skived until the outer surface of thecoupling wire 160D is exposed. This process creates skive pocket 310.Pocket 310 is filled with electrically conductive material 320 to createan electrically conductive pathway between electrode 150D andelectrically conducting element 160D.

Other methods known in the art for electrically coupling the electrodes150 and electrically conducting elements 160 are within the scope ofthis invention. Examples of coupling methods include spot welding theelectrode 150 to the conducting element 160, soldering and mechanicalcrimping, among other techniques. Other electrically conducting elementconfigurations are also within the scope of this invention. Formanufacturing efficiencies, for example, shaft 25 may be extruded withall electrically conducting elements 160 embedded in the shaft forsubstantially the entire length of the catheter shaft 25. Only theelectrode 150 to which the conducting element 160 is coupled will beactivated when the electrical circuit is energized. Those segments ofthe electrically coupling elements 160 distal of the electrode 150connection will not generate an electrical field of sufficient intensityto induce a clinical effect when activated since they are not connectedto any other electrodes.

FIG. 4 depicts the electrical field pattern created when electricalpulses are applied to the catheter 10 shown in FIG. 3A. In theembodiment shown, electrical pulses may be simultaneously applied to allelectrodes 150A-150F with alternating polarity. As an example, electrode150F may have a positive polarity, electrode 150E a negative polarity,electrode 150D a positive polarity, electrode 150C a negative polarity,electrode 150B a positive polarity and electrode 150A a negativepolarity. This arrangement creates the electrical field patternillustrated by field gradient lines 210, 220 and 230. The voltage pulsegenerator (not shown) is configured to generate electrical pulsesbetween electrodes in an amount which is sufficient to induceirreversible electroporation of fibrin sheath smooth muscle cellswithout creating a clinically significant thermal effect to thetreatment site. Specifically, the electrical pulses will createpermanent openings in the smooth muscles cells comprising the fibrinsheath, thereby invoking cell death without creating a clinicallysignificant thermal effect. The smooth muscle cells will remain in situand are subsequently removed by natural body processes.

The strongest (defined as volts/cm) electrical field is nearest to theelectrodes 150 and is depicted by gradient line 210 in FIG. 4. As thedistance away from the electrode 150 increases, the strength of theelectrical field decreases. Gradient line 230 represents the outerperimeter of irreversible electroporation effect and as such defines theouter boundary of cell kill zone. As an example, any fibrin or otherbio-film growth on the surface of the catheter within the outerperimeter 230 will undergo cell death by irreversible electroporation.

Because the voltage pulse generation pattern from the generator does notgenerate damaging thermal effect, and because the voltage pulses onlyablate living cells, the treatment does not damage blood, blood vesselsor other non-cellular or non-living materials such as the venouscatheter itself.

By utilizing separate electrically conducting elements 160 for eachelectrode 150, different fibrin sheath growth 200 segments may betreated independently. For example, a computer (not shown) within thegenerator can control the firing of each electrode pair independentlyand according to a predetermined pattern. Alternatively, the creation ofa series of electrical fields may be accomplished by sequentially firingpairs of electrodes within one treatment session to ensure that theentire length of the fibrin sheath is treated. Sequentially polarizingand applying electrical energy to a subset of the total number ofelectrodes as described herein may be used to target fibrin growth on aspecific segment of the catheter shaft. As an example, FIG. 5 depictsthe electrical fields created when electrical pulses are applied to twoelectrodes only. Electrode 150B may be set to have a positive polarityand electrode 150C a negative polarity. When electrical pulses areapplied to these two electrodes, an electrical field pattern is createdas illustrated by gradient lines 210, 220 and 230. Fibrin sheathbuild-up within the outer perimeter of gradient line 230 will beeffectively destroyed.

In another aspect of the invention, the device and method can be used tocause the destruction of infectious cells, such as catheter-relatedbacteremia, that have grown around the indwelling catheter. Theseinfectious cells can be located anywhere along the indwelling shaft.Research has also shown that infectious cells can form in combinationwith fibrin sheath growths, because fibrin sheath can enhancecatheter-related bacteremia by providing an interface for adherence andcolonization. These pathogens may then produce a “biofilm” which isimpenetrable to systemic antibiotics leading to a cause of catheterdysfunction, subsequent removal, and the attendant increase in morbidityand mortality. Referring again to FIG. 4, the pulse parameters thatcharacterize the field gradient line can be adjusted to vary thetreatment zone according to the location of the fibrin sheath growthand/or infectious cells to be destroyed. Furthermore, in someembodiments of the invention, the electrodes can be positioned at anylocation necessary to destroy any such infectious cells that have grownaround the indwelling catheter. For example, the electrodes can bepositioned at a proximal section of the indwelling catheter for treatinginfectious cells, that have grown around the tunneled portion of thecatheter. In addition, the electrodes can be positioned to destroyinfectious cells that have grown near the insertion site of theindwelling catheter.

In another aspect of the invention, by periodically administering theelectrical pulses according to a predetermined schedule, fibrin sheathgrowth on the catheter shaft 20 can be prevented altogether. As anexample, the formation of a fibrin sheath may occur as early as 24 hoursafter catheter implantation. Smooth muscle cells develop within sevendays. Application of electrical pulses applied to fibrin sheath atregular intervals post-implantation may be effective in preventingfibrin sheath growth during the catheter implantation period.

Referring now to FIG. 6A and 6B, FIG. 6A is a plan view of anelectroporation probe 600 representing another embodiment of the currentinvention. In this embodiment an electroporation probe 600 is comprisedof an electrical connector 601, a flexible shaft body 602 on which twoelectrodes 603 and 604 are positioned in a coaxial arrangement with theshaft, and a distal end or tip 605. The electrodes are preferablypositioned near a distal section of the shaft. As previously describedelectrically conductive elements 606 and 607 extend longitudinally fromthe electrical connector 601 to the electrodes 603 and electrode 604respectively. The electrically conductive elements 606 and 607 may beembedded within the wall of the shaft 602, as previously described, oralternatively may be insulated and positioned within a lumen of shaft602.

FIG. 6B is a partial longitudinal cross-sectional view of the distalsegment of a venous catheter 11 with the distal section of electrodeprobe 600 of FIG. 6A inserted through the catheter lumen 16 andpositioned within a fibrin sheath formation 200. To destroy the fibrinsheath 200, the electrode probe 600 is inserted into the catheter lumen16 and advanced through the distal end hole 26. Electrode probe distaltip 605 may be tapered to provide a non-traumatic leading edge capableof advancing through the sheath formation 200. Electrodes 603 and 604are positioned within the fibrin sheath formation 200 such that whenelectrical pulses are applied, an electrical field (not shown) will becreated that encompasses the fibrin sheath 200 in its entirety. Afterthe electroporation process has destroyed the fibrin sheath, the probeis removed from the catheter. Alternatively, cytotoxic agents may beadministered through lumen 16 and directed into the fibrin formation.Electroporation pulses may be applied to reversibly electroporate thesmooth muscle cells of sheath 200, creating a pathway through the cellmembrane for the agent to enter the cell.

The embodiment illustrated in FIGS. 6A and 6B is particularlyadvantageous when treating a fibrin sheath formation that has advancedinto the lumen of the catheter and occludes the end holes and/or sideholes of the catheter. Another advantage of the embodiment of FIG. 6A isthat the probe is a separate device inserted into the patient throughthe implanted catheter only when treatment is required and then isremoved immediately after treatment. The probe is not part of theimplanted catheter device and is removed immediately after treatment.Utilizing a separate device to perform electroporation reduces thepossibility of electrode or conducting wire damage due to long termimplantation as well as simplifying the manufacturing of the device andcosts associated with the manufacture.

FIGS. 7A-7C illustrate a third embodiment of the present inventionwherein the electroporation probe 700 is comprised of deployableelectrodes. As with the previous embodiment, the electroporation probe700 is inserted into the lumen of a catheter prior to the application ofelectrical pulses, and is removed after treatment. Referring first toFIG. 7A, electrode probe 700 is comprised of an electrical connector hub712, an outer sheath 701 extending from the hub 712 to a distal end hole702, and a plurality of electrically conducting elements 709 and 704arranged within the outer sheath 701 and within a lumen. Electricallyconducting elements 709 and 704 are connected proximally to theelectrical connector/hub 712 and extend distally within the outer sheath701 for substantially the entire length of the sheath. Insulatingsleeves 707 and 703 coaxially surround electrically conducting elements709 and 704 from the hub 712 to insulation distal ends 721 and 723.Un-insulated portions 711 and 705 of electrically conducting elements709 and 704 extend distally. Portions 711 and 705, being un-insulated,act as electrodes when the electrical circuit is energized.

Button 713 on hub 712 is used to deploy and retract the electricallyconducting elements 709 and 704 relative to the outer sheath 701. Theundeployed position of electroporation probe 700 is illustrated in FIG.7A. As shown, the electrically conducting elements 709 and 704 arecompletely contained within the lumen of the outer sheath 701 includingthe un-insulated portions 711 and 705. The fully deployed position ofthe electrode probe 700 is illustrated in FIG. 7B. Button 713 isadvanced distally to deploy the distal sections of electricallyconducting element 709 and 704 out of the distal end hole 702 of outersheath 701. When fully deployed, the distal section of the electricallyconducting elements 709 and 704 extend outwardly from end hole 702, witha profile that curves outwardly and then extends proximally in asubstantially parallel relationship with the longitudinal axis of theprobe 700. The distal portion of insulating sleeves 707 and 703 form atleast part of the curve terminating at points 721 and 723. Theun-insulated portions 711 and 705 form the active electrodes and extendfrom insulation end points 721 and 723 in a proximal direction adjacent(such as parallel to) the outer wall of outer sheath 701.

Electrically conductive elements 704 and 709 may be formed of anysuitable electrically conductive material including but not limitedstainless steel, gold, silver and other metals including shape-memorymaterials such as nitinol. Nitinol is an alloy with super-elasticcharacteristics which enables it to return to a pre-determined expandedshape upon release from a constrained position. The outer sheath 701constrains the distal segments of the undeployed electrically conductiveelements 704 and 709 in a substantially straight distal configuration.Once the electrodes are deployed from the distal end of the outer sheath701 as previously described, the distal sections of electricallyconductive elements 704 and 709 form the “J-hook” curved profile shownin FIG. 7B.

FIG. 7C illustrates a partial longitudinal cross-sectional view of acatheter 11 with the electrode probe 700 in a deployed position. In use,the undeployed electrode probe 700 is inserted into lumen 18 of catheter11 and advanced to the distal end hole 28. Once correctly positioned,button 713 (shown in FIG. 7B) is advanced in the direction shown by thehub arrow to deploy the distal sections of electrically conductingelements 709 and 704 outside of the outer sheath 701 and the catheterdistal end hole 28. When fully deployed, the exposed segments 711 and705 of electrically conducting elements 709 and 704 extend in a proximaldirection adjacent to and parallel to the outer wall of catheter shaft25.

FIG. 8 is an enlarged end view of the catheter of FIG. 7C depicting theelectrical fields created when electrical pulses are applied toelectrode probe 700. Application of pulses creates an electrical fieldpattern between the un-insulated portions 711 and 705 (shown in FIG. 7C)of the electrically conducting elements. This arrangement creates theelectrical field pattern illustrated by field gradient lines 210, 220and 230. The strongest (defined as volts/cm) electrical field is nearestto the active electrodes and is depicted by gradient line 210. As thedistance away from the electrodes increase, the strength of theelectrical field decreases. Gradient line 230 represents the outerperimeter of irreversible electroporation effect and as such defines theouter boundary of cell kill zone. As an example, any fibrin or otherbio-film growth on the surface of the catheter within the outerperimeter 230 will undergo cell death by irreversible electroporation.

If fibrin sheath has formed around end hole 26, electrode probe 700 maybe inserted into lumen 16 (shown in FIG. 7C), positioned and thenelectrodes deployed as previously described. Application of electricalpulses will create an electrical field as shown in FIG. 8, except thefield will be centered around end hole 26 rather than end hole 28. It isalso within the scope of this invention to utilize two electrode probesof opposite polarity with one probe placed in each lumen. In thisembodiment, the electrical field may be created between the two probes,creating an electrical field similar to that illustrated in FIG. 4.

The deploying electrode probe 700 illustrated in FIGS. 7A-C and 8 isparticularly advantageous in destroying fibrin build-up along the outersurface of the distal segment of an implanted catheter. Probe 700 may beused to clear fibrin sheath formations from each lumen of a catheter aswell as to irreversibly electroporate fibrin sheath occluding side holeslocated near the distal end of the catheter. The number of electricallyconducting elements 704 and 709 may be varied to accommodate varioussize catheters and fibrin sheath volumes. In addition, the length of theexposed segment 711 and 705 may be adjusted based on the catheter lengthand/or the length of the fibrin formation extending proximally from thedistal end holes of the catheter. It is also within the scope of thisinvention to configure a probe with two deployable electrodes which,when deployed, are arranged at an angle relative to each other of lessthan 180 degrees (i.e., not parallel to each other). After applyingelectrical pulses to create an electrical field pattern, the probe maybe rotated and pulse applied again to create a second electrical fieldpattern. This process is repeated until the entire 360 degreecircumference of the outer surface of the catheter has been treated. Itis also understood that any of the embodiments illustrated may be usedto reversibly electroporate the fibrin sheath for the purpose ofintroducing therapeutic agents into the smooth muscle cells.

FIG. 9 illustrates the procedural steps associated with performingirreversible or reversible electroporation treatment using the devicewhich is depicted in FIGS. 1-5. After the fibrin sheath formation hasbeen detected and the location of the formation determined usingultrasound or fluoroscopic imaging, electrical connector 500 isconnected to an electrical generator (801) using an extension cable.This completes an electrical circuit between the electrodes 150 and thegenerator via the electrically conducting elements 160. Electricalpulses are applied across the electrodes in the desired pattern toelectroporate the smooth muscle cells of the fibrin sheath (802). If theelectrical generator treatment parameters are set to deliver electricalpulses within the reversible range (803), therapeutic agents may beinjected through the catheter lumens (804) and pass into the fibrinsheath formation through either the side holes or end holes of thecatheter. After treatment, the extension cable is disconnected from theelectrical connector (805). Non-thermal death of the smooth muscle cellswill occur within the first twenty-four hours after electroporationtreatment followed by a cellular breakdown of the fibrin sheath.

Referring now to FIG. 10, the method of performing electroporationtreatment using the device depicting in FIGS. 6A-B or FIG. 7A-C isillustrated. After the fibrin sheath formation has been detected and thelocation of the formation determined using ultrasound or fluoroscopicimaging, electrode probe 600 (FIGS. 6A-B) or 700 (FIGS. 7A-C) isinserted into the venous catheter (901). The probe is then positionedrelative to the fibrin sheath location as previously described. Theelectrical connector 601 or 712 is then connected to an electricalgenerator using an extension cable (902). If using electrode probe 700,the electrodes are deployed (904) and positioned outside of the cathetershaft as shown in FIG. 7C. Electrical pulses are then applied across theelectrodes (905) creating a field gradient sufficient to non-thermallyelectroporate the smooth muscle cells present in the fibrin sheath. Ifthe electrical generator treatment parameters are set to deliverelectrical pulses within the reversible range (906), therapeutic agentsmay be injected through the catheter lumen (907) passing into the fibrinsheath formation through either the side holes or end holes of thecatheter. Alternatively, the electroporation probe may be configured toinclude a lumen through which agents may be administered. If using probe700, the electrodes are then retracted (908) within the outer sheath701. After the procedure is complete, the probe is removed from thecatheter (909). Non-thermal death of the smooth muscle cells occur afterelectroporation treatment followed by a cellular breakdown of the fibrinsheath.

In one embodiment, the electroporation pulses can be synchronouslymatched to specifically repeatable phases of the cardiac cycle toprotect cardiac cellular functioning. See, for example, U.S. patentapplication Ser. No. 61/181,727, filed May 28, 2009, entitled “AlgorithmFor Synchronizing Energy Delivery To The Cardiac Rhythm”, which is fullyincorporated by reference herein. This feature is especially useful whenthe electroporation pulses are delivered in a location that is near theheart. FIG. 11 illustrates a treatment setup for a patient forsynchronization of the delivery of electroporation pulses with aspecific portion of the cardiac rhythm. Electrocardiogram (ECG) leads17, 19, 21 are adapted to be attached to the patient for receivingelectrical signals which are generated by the patient's cardiac cycle.The ECG leads transmit the ECG electrical signals to anelectrocardiogram unit 23. The electrocardiogram unit 23 can transmitthis information to a synchronization device 25 which can includehardware or software to interpret ECG data. If the synchronizationdevice 25 determines that it is safe to deliver electroporation pulses,it sends a control signal to a pulse generator 27. The pulse generator27 is adapted to connect to electrical connector 500 for deliveringelectroporation pulses. Each of the synchronization device 25 and pulsegenerator 27 can be implemented in a computer so that they can beprogrammed.

The present invention affords several advantages. Fibrin sheath growthsare destroyed without having to remove the catheter from the patient.The treatment is minimally-invasive and highly efficacious. Becauseirreversible electroporation does not create thermal activity, thecatheter is not damaged by the treatment. Fibrin sheath growths aretreated quickly, and the catheters can be maintained according to apredetermined schedule to insure that the distal openings remain clear.

Although the irreversible electroporation device and method has beendescribed herein for use with dual-lumen catheters, it should beunderstood that the irreversible electroporation device can be used withsingle lumen catheters or multiple-lumen catheters. Another type ofvenous catheter which is prone to fibrin sheath formation is a venouscatheter that is connected to an implanted port. An example of a venouscatheter attached to an implanted port is disclosed in U.S. Pat.Application Publication No. 2007/0078391, which is incorporated hereinby reference. Electrode probe devices described in FIGS. 6A-B and 7A-Cmay be used to remove fibrin sheath from catheter shafts connected toimplanted port devices. In the case of port devices, the probe may beinserted through a needle lumen that has been inserted into the septum.The probe device may include a guidewire lumen to assist in trackingthrough the stem channel and into the catheter shaft lumen. Fibrinsheath formations on PICC lines or other central venous catheters mayalso be destroyed using the devices and methods illustrated herein.

While the embodiments shown use pulses that cause IRE, persons ofordinary skill in the art will appreciate that other types of pulses canbe used for the destruction of the fibrin sheath growths. In particular,ultrashort sub-microsecond pulses (pulses of less than 1 microsecond induration) can be used to induce apoptosis that cause damage to theintracellular structures such as a cell nucleus.

The above disclosure is intended to be illustrative and not exhaustive.This description will suggest many modifications, variations, andalternatives may be made by ordinary skill in this art without departingfrom the scope of the invention. Those familiar with the art mayrecognize other equivalents to the specific embodiments describedherein. Accordingly, the scope of the invention is not limited to theforegoing specification.

What is claimed:
 1. A method comprising: connecting a generator to a atleast two electrodes, wherein the electrodes are configured to bepositioned on an implanted medical device; and applying a predeterminedset of electrical pulses to the at least two electrodes; wherein thepredetermined set of electrical pulses are configured to non-thermallyablate an undesirable cellular growth that may have formed around theimplanted medical device.
 2. The method of claim 1, wherein thenon-thermal ablation is irreversible electroporation.
 3. The method ofclaim 2, wherein the predetermined set of electrical pulses comprise avoltage up to 3,000 volts and at least 10 total pulses.
 4. The method ofclaim 1, wherein the undesirable cellular growth may comprise a fibrinsheath, infectious cells, a biofilm, or smooth muscle cells.
 5. Themethod of claim 1, wherein applying a predetermined set of electricalpulses to the at least two electrodes is configured to prevent theremoval of the implanted medical device.
 6. The method of claim 1,further comprising the step of: applying the predetermined set ofelectrical pulses at a predetermined schedule.
 7. The method of claim 6,wherein the predetermined set of electrical pulses is configured to beapplied by the generator simultaneously to the at least two electrodes.8. The method of claim 7, further comprising the step of: alternatingpolarity of the at least two electrodes.
 9. The method of claim 1,wherein the implanted medical device may comprise a dialysis catheter, aport catheter, electrocardiogram leads, a central venous catheter, or aperipherally inserted central catheter.
 10. The method of claim 1,wherein the predetermined set of electrical pulses comprises a pulselength of less than 1 microsecond.
 11. A method comprising: connecting agenerator to a at least two electrodes, wherein the electrodes areconfigured to be positioned on an implanted medical device; and applyinga predetermined set of electrical pulses to the at least two electrodes;wherein the predetermined set of electrical pulses are configured toprevent undesirable cellular growth that may have formed around theimplanted medical device.
 12. The method of claim 11, further comprisingthe step of: applying the predetermined set of electrical pulses at apredetermined schedule.
 13. The method of claim 12, wherein theundesirable cellular growth may comprise a fibrin sheath, infectiouscells, a biofilm, or smooth muscle cells.
 14. The method of claim 1,wherein the predetermined set of electrical pulses comprises a pulselength of at least 1 microsecond, a voltage up to 3,000 volts, and atleast 10 total pulses.
 15. A method comprising: connecting a generatorto a at least two electrodes; advancing the electrodes through a lumenof an implanted medical device to a target area; and applying apredetermined set of electrical pulses to the at least two electrodes;wherein the predetermined set of electrical pulses are configured tonon-thermally ablate an undesirable cellular growth that may have formednear the implanted medical device at the target area.
 16. The method ofclaim 15, further comprising the step of: applying the predetermined setof electrical pulses at a predetermined schedule.
 17. The method ofclaim 15, wherein the predetermined set of electrical pulses comprises apulse length of at least 1 microsecond, a voltage up to 3,000 volts, andat least 10 total pulses.
 18. The method of claim 17, wherein theundesirable cellular growth may comprise a fibrin sheath, infectiouscells, a biofilm, or smooth muscle cells.
 19. The method of claim 18,wherein the electrodes are co-axially advanced through the lumen of theimplanted medical device to the target area.
 20. The method of claim 19,wherein the non-thermal ablation is irreversible electroporation.